Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

A broadly applicable [18F]trifluoromethylation of aryl and heteroaryl iodides for PET imaging

Nature Chemistry volume 5, pages 941–944 (2013)Cite this article

Subjects

Abstract

Molecules labelled with the unnatural isotope fluorine-18 are used for positron emission tomography. Currently, this molecular imaging technology is not exploited at its full potential because many 18F-labelled probes are inaccessible or notoriously difficult to produce. Typical challenges associated with 18F radiochemistry are the short half-life of 18F (<2 h), the use of sub-stoichiometric amounts of 18F, relative to the precursor and other reagents, as well as the limited availability of parent 18F sources of suitable reactivity ([18F]F– and [18F]F2). There is a high-priority demand for general methods allowing access to [18F]CF3-substituted molecules for application in pharmaceutical discovery programmes. We report the development of a process for the late-stage [18F]trifluoromethylation of (hetero)arenes from [18F]fluoride using commercially available reagents and (hetero)aryl iodides. This [18F]CuCF3–based protocol benefits from a large substrate scope and is characterized by its operational simplicity.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Direct trifluoromethylation of aryl and heteroaryl iodides.
Figure 2: Cu(I)-mediated [18F]trifluoromethylation of arenes, heteroarenes and pyrimidine-2,4(1H,3H)-dione with [18F]fluoride.
Figure 3: [18F]Labelling of fluoxetine and flutamide.

Similar content being viewed by others

References

  1. Phelps, M. E. Positron emission tomography provides molecular imaging of biological processes. Proc. Natl Acad. Sci. USA 97, 9226–9233 (2000).

    Article  CAS  Google Scholar 

  2. Ametamey, S. M., Honer, M. & Schubiger, P. A. Molecular imaging with PET. Chem. Rev. 108, 1501–1516 (2008).

    Article  CAS  Google Scholar 

  3. Matthews, P. M., Rabiner, E. A., Passchier, J. & Gunn, R. N. Positron emission tomography molecular imaging for drug development. Br. J. Clin. Pharmacol. 73, 175–186 (2012).

    Article  CAS  Google Scholar 

  4. Wong, D. F., Tauscher, J. & Gründer, G. The role of imaging in proof of concept for CNS drug discovery and development. Neuropsychopharmacol. Rev. 34, 187–203 (2009).

    Article  CAS  Google Scholar 

  5. Miller, P. W., Long, N. J., Vilar, R. & Gee, A. D. Synthesis of 11C, 18F, 15O, 13N radiolabels for positron emission tomography. Angew. Chem. Int. Ed. 47, 8998–9033 (2008).

    Article  CAS  Google Scholar 

  6. Tredwell, M. & Gouverneur, V. 18F labeling of arenes. Angew. Chem. Int. Ed. 51, 11426–11437 (2012).

    Article  CAS  Google Scholar 

  7. Müller, K., Faeh, C. & Diederich, F. Fluorine in pharmaceuticals: looking beyond intuition. Science 317, 1881–1886 (2007).

    Article  Google Scholar 

  8. Purser, S., Moore, P. R., Swallow, S. & Gouverneur, V. Fluorine in medicinal chemistry. Chem. Soc. Rev. 37, 320–330 (2008).

    Article  CAS  Google Scholar 

  9. Lee, E. et al. A fluoride-derived electrophilic late-stage fluorination reagent for PET imaging. Science 334, 639–642 (2011).

    Article  CAS  Google Scholar 

  10. Lee, E., Hooker, J. M. & Ritter, T. Nickel-mediated oxidative fluorination for PET with aqueous [18F]fluoride. J. Am. Chem. Soc. 134, 17456–17458 (2012).

    Article  CAS  Google Scholar 

  11. Gao Z. et al. Metal-free oxidative fluorination of phenols with [18F]fluoride. Angew. Chem. Int. Ed. 51, 6733–6737 (2012).

    Article  CAS  Google Scholar 

  12. Kilbourn, M. R., Pavia, M. R. & Gregor, V. E. Synthesis of fluorine-18 labeled GABA uptake inhibitors Appl. Radiat. Isot. 41, 823–828 (1990).

    Article  CAS  Google Scholar 

  13. Prabhakaran, J. et al. Synthesis and in vivo evaluation of [18F]-4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide as a PET imaging probe for COX-2 expression. Bioorg. Med. Chem. 15, 1802–1807 (2007).

    Article  CAS  Google Scholar 

  14. Angelini, G., Speranza, M., Shiue, C-Y. & Wolf, A. P. H18F+Sb2O3: a new selective radiofluorinating agent. J. Chem. Soc. Chem. Commun. 924–925 (1986).

  15. Angelini, G., Speranza, M., Wolf, A. P. & Shiue, C-Y. Synthesis of N-(α,α,α-tri[18F]fluoro-m-tolyl)piperazine. A potent serotonin agonist. J. Label. Compd. Radiopharm. 28, 1441–1448 (1990).

    Article  CAS  Google Scholar 

  16. Furuya, T., Kamlet, A. S. & Ritter, T. Catalysis for fluorination and trifluoromethylation. Nature 473, 470–477 (2011).

    Article  CAS  Google Scholar 

  17. Tomashenko, O. A. & Grushin, V. V. Aromatic trifluoromethylation with metal complexes. Chem. Rev. 111, 4475–4521 (2011).

    Article  CAS  Google Scholar 

  18. Wu, X-F., Neumann, H. & Beller, M. Recent developments on the trifluoromethylation of (hetero)arenes. Chem. Asian J. 7, 1744–1754 (2012).

    Article  CAS  Google Scholar 

  19. Mizuta, S. et al. Catalytic decarboxylative fluorination for the synthesis of tri- and difluoromethyl arenes. Org. Lett. 15, 2648–2651 (2013).

    Article  CAS  Google Scholar 

  20. Teare, H. et al. Radiosynthesis and evaluation of [18F]selectfluor bis(triflate). Angew. Chem. Int. Ed. 49, 6821–6824 (2010).

    Article  CAS  Google Scholar 

  21. Bergman, J. & Solin, O. Fluorine-18-labeled fluorine gas for synthesis of tracer molecules. Nucl. Med. Biol. 24, 677–683 (1997).

    Article  CAS  Google Scholar 

  22. MacNeil, J. G. Jr & Burton, D. J. Generation of trifluoromethylcopper from chlorodifluoroacetate. J. Fluor. Chem. 55, 225–227 (1991).

    Article  CAS  Google Scholar 

  23. Su, D-B., Duan, J-X., Yu, A-J. & Chen, Q-Y. Synthesis of functionalized long-chain perfluoroalkanes from methyl halofluoroacetates: a process of difluorocarbene insertion into copper–carbon bonds. J. Fluor. Chem. 65, 11–14 (1993).

    Article  CAS  Google Scholar 

  24. Duan, J-X., Su, D-B. & Chen, Q-Y. Trifluoromethylation of organic halides with methyl halodifluoroacetates—a process via difluorocarbene and trifluoromethide intermediates. J. Fluor. Chem. 61, 279–284 (1993).

    Article  CAS  Google Scholar 

  25. Duan, J-X., Su, D-B., Wu, J-P. & Chen, Q-Y. Synthesis of trifluoromethyl aryl derivatives via difluorocarbene precursors and nitro-substituted aryl chlorides. J. Fluor. Chem. 66, 167–169 (1994).

    Article  CAS  Google Scholar 

  26. Oishi, M., Kondo, H. & Amii, H. Aromatic trifluoromethylation catalytic in copper. Chem. Commun. 1909–1911 (2009).

  27. Morimoto, H., Tsubogo, T., Litvinas, N. D. & Hartwig, J. F. A broadly applicable copper reagent for trifluoromethylations and perfluoroalkylations of aryl iodides and bromides. Angew. Chem. Int. Ed. 50, 3793–3798 (2011).

    Article  CAS  Google Scholar 

  28. Chu, L. & Qing, F-L. Copper-catalyzed direct C–H oxidative trifluoromethylation of heteroarenes. J. Am. Chem. Soc. 134, 1298–1304 (2012).

    Article  CAS  Google Scholar 

  29. Naimi, E., Duan, W., Wiebe, L. I. & Knaus, E. E. Synthesis of unnatural 7-substituted-1-(2-deoxy-β-D-ribofuranosyl)isocarbostyrils: ‘thymine replacement’ analogs of deoxythymidine for evaluation as antiviral and anticancer agents. Nucleosides Nucleotides Nucleic Acids 20, 1533–1553 (2001).

    Article  CAS  Google Scholar 

  30. Nagib, D. A. & MacMillan, D. W. C. Trifluoromethylation of arenes and heteroarenes by means of photoredox catalysis. Nature 480, 224–228 (2011).

    Article  CAS  Google Scholar 

  31. Ji, Y. et al. Innate C–H trifluoromethylation of heterocycles. Proc. Natl Acad. Sci. USA 108, 14411–14415 (2011).

    Article  CAS  Google Scholar 

  32. Hammadi, A. & Crouzel, C. Synthesis of [18F]-(S)-fluoxetine: a selective serotonine uptake inhibitor. J. Label. Compd. Radiopharm. 33, 703–710 (1993).

    Article  CAS  Google Scholar 

  33. Jacobson, O. et al. Prostate cancer PET bioprobes: synthesis of [18F]-radiolabeled hydroxyflutamide derivatives. Bioorg. Med. Chem. 13, 6195–6205 (2005).

    Article  CAS  Google Scholar 

  34. Lapi, S. E. & Welch, M. J. A historical perspective on the specific activity of radiopharmaceuticals: what have we learned in the 35 years of the ISRC? Nucl. Med. Biol. 40, 314–320 (2013).

    Article  CAS  Google Scholar 

  35. Anderson, C. J. & Ferdani, R. Copper-64 radiopharmaceuticals for PET imaging of cancer: advances in preclinical and clinical research. Cancer Biother. Radiopharm. 24, 379–393 (2009).

    Article  CAS  Google Scholar 

  36. Zeng, D., Zeglis, B. M., Lewis, J. S. & Anderson, C. J. The growing impact of bioorthogonal click chemistry on the development of radiopharmaceuticals. J. Nucl Med. 54, 829–832 (2013).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

Financial support was provided by Imanova, GlaxoSmithKline, the European Union (grant PIIF-GA-20100274903 to S.M.), the Engineering and Physical Sciences Research Council (M.T.) and the Cancer Research UK (M.T.). The authors thank P. Holdship (Department of Earth Sciences, University of Oxford) for the ICP-MS measurements. V.G. is a recipient of a Royal Society Wolfson Research Merit Award.

Author information

Authors and Affiliations

  1. Imanova, Burlington Danes Building, Imperial College London, Hammersmith Hospital, Du Cane Road, London, W12 0NN, UK

    Mickael Huiban & Jan Passchier

  2. Chemistry Research Laboratory, University of Oxford, 12 Mansfield Road, Oxford, OX1 3TA, UK

    Matthew Tredwell, Satoshi Mizuta & Véronique Gouverneur

  3. GlaxoSmithKline, 898 Halei Road, Zhangjiang Hi-Tech Park, Shanghai, 201203, Pudong, China

    Zehong Wan & Xiaomin Zhang

  4. Advion BioSystems, 10 Brown Road, Suite 101, New York, 14850, Ithaca, USA

    Thomas Lee Collier

Authors
  1. Mickael Huiban
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Matthew Tredwell
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Satoshi Mizuta
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Zehong Wan
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Xiaomin Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Thomas Lee Collier
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Véronique Gouverneur
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Jan Passchier
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

M.H., M.T. and S.M. performed and analysed experiments. All authors contributed to the design of experiments to develop this reaction and probe its utility. V.G. and J.P. prepared the manuscript.

Corresponding authors

Correspondence to Véronique Gouverneur or Jan Passchier.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary information

Supplementary information (PDF 2866 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Huiban, M., Tredwell, M., Mizuta, S. et al. A broadly applicable [18F]trifluoromethylation of aryl and heteroaryl iodides for PET imaging. Nature Chem 5, 941–944 (2013). https://doi.org/10.1038/nchem.1756

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nchem.1756

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing